In FY 2015 we used our humanized mouse model to investigate a new therapeutic against HIV infections. The model utilizes severely immunocompromised mice reconstituted with human thymic and liver tissue, which establishes human lymphocytic and monocytic populations susceptible to HIV infection. The mice support both intravenous and mucosal HIV infection and develop HIV-specific B and T cell immunity. A distinct advantage of this model is that the mice do not develop graft versus host disease and can therefore be used in long-term studies of HIV infection not previously possible. We investigated the therapeutic use of natural human alpha interferon subsets to treat acute HIV infections. We found some subsets to be extremely potent in their suppression of HIV while other subtypes were ineffective. The mechanisms of IFN efficacy were investigated and showed associations with the activation of intrinsic and innate immune responses rather than adaptive immune responses. Since the IFN functions via separate mechanisms as the currently used antiretroviral drugs, the addition of IFN therapy to commonly used antiretroviral drug therapy could provide increased viral control and reductions in chronic virus levels.